Traumatic brain injury (TBI) is a significant health concern affecting 1.4 million people in the United States. Although much is known about the pathophysiological mechanisms underlying TBI, few therapeutic strategies have been successfully translated to the clinical setting. TBI initiates multiple injury cascades in the brain including inflammatory processes that exacerbate the initial injury. Our laboratory has found that post- traumatic temperature manipulations can dramatically attenuate trauma-induced inflammatory processes and significantly improve outcome after TBI. Mild to moderate hypothermia reduces the infiltration of inflammatory cells into the injured brain and attenuates elevations of the pro-inflammatory cytokine, interleukin-1 (IL-1). The overall objective of this revised application is to identify the inflammatory signaling events that are regulated by hypothermia after TBI and whether this influences clinically relevant functional outcomes. In Aim 1 we will determine the effects of hypothermia on the formation of posttraumatic epilepsy (PTE) after TBI which occurs in as many as 1 in 4 brain-injured patients. In experimental models of epilepsy, inflammation increases in the brain as a consequence of seizures and anti-inflammatory treatments reduce seizure formation. Thus, we will assess whether hypothermia therapy after TBI modulates seizure threshold, as well as improves the histopathological and electrophysiological changes in the brain that contribute to seizure formation. In Aim 2 we will investigate whether hypothermia therapy after TBI attenuates blood-brain barrier (BBB) permeability and the accumulation and activation of inflammatory cells in the brain such as monocyte-derived macrophages, polymorphonuclear leukocytes, microglia, and astrocytes. A new battery of BBB probes will be used to thoroughly characterize the extent to which hypothermia reduces BBB permeability. In Aim 3 we will directly test a causal relationship between systemic and endogenous inflammatory mechanisms initiated after TBI and the development of PTE. We will also assess the effects of elevating systemic levels of IL-1 on PTE since systemic levels of pro-inflammatory cytokines are a common consequence of multi-organ trauma in the TBI patient population. This project is highly supported by an established group of investigators who provide a wealth of expertise in TBI, laboratory techniques, and temperature manipulations. This research will provide important information regarding the use of therapeutic hypothermia in both the acute and chronic injury setting. The proposed studies will provide novel information regarding the development of seizures after TBI and determine how hypothermia therapy may improve this debilitating consequence of TBI.